Rational Drug Design Using the 3D Shape of Proteins to Design Drugs that Inhibit Protein Function Before you start this activity, make sure you have the program Cn3D installed on your computer. Download Cn3d from this site Examples of Protein Function Hormones
Using the 3D Shape of Proteins to Design Drugs that Inhibit Protein Function
Before you start this activity, make sure you have the program Cn3D installed on your computer.
Download Cn3d from this site
Insulin binds to receptors on cell membranes signalling cells to take up glucose from the blood
Protein ChannelsRegulate movement of substances across the plasma membrane. E.g. The CFTR protein pumps ions across membranes
Haemoglobin (far right) in red blood cells transports oxygen to cells around the body
Hydrogen peroxide, a natural product of metabolism in your cells, is highly toxic in high concentrations and must be removed quickly!
Add ferric ions (Fe 3+)
Rate increases 30 000-fold
Rate increases 100 000 000-fold
Location of active site where
Hydrogen peroxide binds
Ripping things apart
Joining things together
Ricin from the seeds of the castor oil plant destroys ribosomes
Funnel web spider toxin: blocks movement of calcium ions.
Each protein has a specific sequence of amino acids that are linked together, forming a polypeptide
Interactions between amino acids in the chain form:
Together usually form the binding and active sites of proteins
Source: io.uwinnipeg.ca/~simmons/ cm1503/proteins.htm
The final protein may be made up of more than one polypeptide chain.
The polypeptide chains may be the same type or different types.
Amylase is a protein that cuts small maltose sugar molecules off starch molecules.
Another enzyme, maltase, is responsible for breaking down the maltose molecules into two simple sugars known as glucose.
Glucose is absorbed into the blood and transported to cells around the body to provide them with energy.
Click on the button on the right to start exploring amylase with its active site blocked by a drug.
Amylase in Cn3D
The Spanish Flu in 1918, killed approximately 50 million people. It was caused by the H1N1 strain of influenza A.
The Asian Flu in 1957 was the H2N2 influenza A strain. Worldwide it is estimated that at least one million people died from this virus.
The Hong Kong Flu in 1968 evolved into H3N2. 750,000 people died of the virus worldwide
Figure 1. Weekly number of influenza and pneumonia deaths per 10 000 000 population in the United States, France, and Australia (black line).
Influenza viruses are named according to the proteins sticking out of their virus coat.
There are two types of protein = Nand H.
N and H have special shapes to perform specific jobs for the virus.
N cuts the links between the viruses and the cell surface so virus particles are free to go and infect more cells.
H attaches to cell surface proteins so virus can enter cell
Proteins on cell surface
Virus genes are released into the cell.
The lung cell is ‘tricked’ into using these genes to make new virus particles.
Human Lung Cell
This link will open a Cn3D file of Neuraminidase with the drug relenza blocking its active site
Link to watch movie
A team of scientists from Melbourne University have patented a toxic chemical from the venom of an Australian Cone Shell.
The chemical, called ACV1, is an analgesic that will help relieve chronic pain. It is more powerful than morphine and is not addictive.
This analgesic will be used to treat pain resulting from nerve injury, post-surgical pain, “phantom limb” pain in amputees, leg ulcers in diabetics or the pain of terminal AIDS or cancer.
ACV1 treats pain by blocking the transmission of pain along our peripheral nervous system
This drug could generate an annual profit of greater than1 billion dollars to the company that develops it!
AcetylcholineThe nerve impulse
3.Influx of Calcium causes acetylcholine to be released into synaptic junction.
2. Sodium ions accumulate causing Calcium ion channels to open.
4. Acetylcholine binds with receptor proteins changing the shape of the ion channel.
5. This opens the sodium ion channel to let in sodium.
6. Sodium ions set off an electrical impulse along the next nerve cell.
7. The pain message is working.
1. Electrical impulse generated along axon – sodium ions (red) rush in and Potassium ions (green) rush out
To block pain we can try to target the ion channels.
Below is an image of a section of a nerve cell cut open to reveal one of the Sodium Ion channels that studs its surface. Let’s slice through an ion channel to show its inner workings..
2 Acetylcholine molecules bind to Receptor binding protein on an ion channel.
The shape of the ion channel protein changes so the Na+ gate opens.
Ions move into the neuron setting off an impulse.
The message is passed on!
You will explore this part of the ion channel.
This is the section that binds acetylcholine &/or drug molecules causing the ion channel to change its shape.
Outside neuronal cell
Cell membrane (Phospholipid bylayer)
Inside neuronal cell
Some conotoxins block acetylcholine (nACh) receptors that stud the surface of neurons. Let’s eplore this ion channel in Cn3D
Follow in the footsteps of Associate Professor Bruce Livett and his team to explore how conotoxins can block nerve impulses, stopping pain.
Ion Channel with
alpha conotoxin A
Alpha conotoxin B